The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGFbeta signalling

Wicks, Stephen J., Haros, Katherine, Maillard, Marjorie, Song, Ling, Cohen, Robert E., ten Dijke, Peter and Chantry, Andrew (2005) The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGFbeta signalling. Oncogene, 24 (54). pp. 8080-8084. ISSN 0950-9232

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Disruption of components in the transforming growth factor-beta (TGF-beta) signalling cascade is a common occurrence in human cancers. TGF-beta pathway activation is accomplished via serine/threonine kinase receptors and intracellular Smad transcription factors. A key regulatory step involves specific ubiquitination by Smurfs that mediate the proteasomal degradation of Smads and/or receptors. Here, we report a novel interaction between Smads and ubiquitin C-terminal hydrolase UCH37, a deubiquitinating enzyme that could potentially reverse Smurf-mediated ubiquitination. In GST pull down experiments, UCH37 bound weakly to Smad2 and Smad3, and bound very strongly to Smad7 in a region that is distinct from the –PY– motif in Smad7 that interacts with Smurf ubiquitin ligases. Endogenous Smad7 and UCH37 formed a stable complex in U4A/JAK1 cells, and FLAG-Smad7 co-immunoprecipitated with HA-UCH37 in transfected HEK-293 cells. In addition, we show that UCH37 can deubiquitinate and stabilize the type I TGF-beta receptor. Furthermore, overexpression of UCH37 upregulates TGF-beta-dependent transcription, and this effect is reversed in cells subject to RNAi-mediated knockdown of endogenous UCH37. These findings support a new role for deubiquitinating enzymes in the control of the TGF-beta signalling pathway, and provide a novel molecular target for the design of inhibitors with therapeutic potential in cancer.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Science > Research Groups > Cells and Tissues
Depositing User: EPrints Services
Date Deposited: 01 Oct 2010 13:37
Last Modified: 22 Apr 2023 01:35
DOI: 10.1038/sj.onc.1208944

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